iBet uBet web content aggregator. Adding the entire web to your favor.
iBet uBet web content aggregator. Adding the entire web to your favor.



Link to original content: https://doi.org/10.1038/25374
Changes in thymic function with age and during the treatment of HIV infection | Nature
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Changes in thymic function with age and during the treatment of HIV infection

Nature volume 396, pages 690–695 (1998)Cite this article

Abstract

The thymus represents the major site of the production and generation of T cells expressing αβ-type T-cell antigen receptors1. Age-related involution2 may affect the ability of the thymus to reconstitute T cells expressing CD4 cell-surface antigens that are lost during HIV infection3; this effect has been seen after chemotherapy and bone-marrow transplantation4,5. Adult HIV-infected patients treated with highly active antiretroviral therapy (HAART) show a progressive increase in their number of naive CD4-positive T cells6,7. These cells could arise through expansion of existing naive T cells in the periphery8 or through thymic production of new naive T cells9,10. Here we quantify thymic output by measuring the excisional DNA products of TCR-gene rearrangement. We find that, although thymic function declines with age, substantial output is maintained into late adulthood. HIV infection leads to a decrease in thymic function that can be measured in the peripheral blood and lymphoid tissues. In adults treated with HAART, there is a rapid and sustained increase in thymic output in most subjects. These results indicate that the adult thymus can contribute to immune reconstitution following HAART.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation of signal-joint and coding-joint TRECs and their detection in lymphocyte populations.
Figure 2: TREC levels in healthy, athymic and HIV-infected individuals.
Figure 3: Changes in signal-joint TREC levels after HAART.

Similar content being viewed by others

References

  1. Picker, L. & Siegelman, M. in Fundamental Immunology (ed. Paul, W. E.) 145–197 (Raven, New York, 1993).

    Google Scholar 

  2. Steinmann, G. Changes in the human thymus during aging. Curr. Top. Pathol. 75, 43–80 (1986).

    Article  CAS  Google Scholar 

  3. Pantaleo, G., Graziosi, C. & Fauci, A. The immunopathogenesis of human immunodeficiency virus infection. New Engl. J. Med. 328, 327–335 (1993).

    Article  CAS  Google Scholar 

  4. Mackall, C. & Gress, R. Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol. Rev. 157, 61–72 (1997).

    Article  CAS  Google Scholar 

  5. Mackall, C.et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. New Engl. J. Med. 332, 143–149 (1995).

    Article  CAS  Google Scholar 

  6. Autran, B.et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277, 112–116 (1997).

    Article  CAS  Google Scholar 

  7. Zhang, Z.-Q.et al. Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc. Natl Acad. Sci. USA 95, 1154–1159 (1998).

    Article  ADS  CAS  Google Scholar 

  8. Haynes, B.et al. Analysis of the role of the adult thymus in reconstitution of peripheral T lymphocytes in human immunodeficiency virus type 1 infection. J. Clin. Invest. (submitted).

  9. McCune, J.et al. High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J. Clin. Invest. 101, 2301–2308 (1998).

    Article  CAS  Google Scholar 

  10. Dybul, M., Kinter, A., Ruiz, M. & Fauci, A. Promethean thymus? J. Clin. Invest. 101, 2299–2300 (1998).

    Article  CAS  Google Scholar 

  11. Kong, F.-K., Chen, C.-L. & Cooper, M. Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation. Immunity 8, 97–104 (1998).

    Article  CAS  Google Scholar 

  12. Livak, F. & Schatz, D. T-cell receptor α locus V(D)J recombination by-products are abundant in thymocytes and mature T cells. Mol. Cell. Biol. 16, 609–618 (1996).

    Article  CAS  Google Scholar 

  13. Takeshita, S., Toda, M. & Ymagishi, H. Excision products of the T cell receptor gene support a progressive rearrangement model of the α/δ locus. EMBO J. 8, 3261–3270 (1989).

    Article  CAS  Google Scholar 

  14. Bogue, M. & Roth, D. B. Mechanism of V(D)J recombination. Curr. Opin. Immunol. 8, 175–180 (1996).

    Article  CAS  Google Scholar 

  15. Verschuren, M.et al. Preferential rearrangements of the T cell receptor-δ-deleting elements in human T cells. J. Immunol. 158, 1208–1216 (1997).

    CAS  PubMed  Google Scholar 

  16. Picker, L.et al. Control of lymphocyte recirculation in man. J. Immunol. 150, 1105–1121 (1993).

    CAS  PubMed  Google Scholar 

  17. Petrie, H., Livak, F., Burtrum, D. & Mazel, S. Tcell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production. J. Exp. Med. 182, 121–127 (1995).

    Article  CAS  Google Scholar 

  18. Piatak, M. Jet al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259, 1749–1754 (1993).

    Article  ADS  CAS  Google Scholar 

  19. Cossarizza, A.et al. Age-related imbalance of virgin (CD45RA+) and memory (CD45R0+) cells between CD4+ and CD8+ T lymphocytes in humans: a study from newborns to centenarians. J. Immunol. Res. 4, 118–126 (1992).

    Google Scholar 

  20. McLean, A. & Michie, C. In vivo estimates of division and death rates of human T lymphocytes. Proc. Natl Acad. Sci. USA 92, 3707–3711 (1995).

    Article  ADS  CAS  Google Scholar 

  21. Schnittman, S.et al. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc. Natl Acad. Sci. USA 87, 6058–6062 (1990).

    Article  ADS  CAS  Google Scholar 

  22. Chun, T., Chadwick, K., Margolick, J. & Siliciano, R. Differential susceptibility of naive and memory CD4+ T cells to the cytopathic effects of infection with human immunodeficiency virus type 1 strain LAI. J. Virol. 71, 4436–4444 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Schnittman, S. M.et al. Evidence for susceptibility of intrathymic T cell precursors to human immunodeficiency virus infection: a mechanism for T4 (CD4) lymphocyte depletion. Trans. Assoc. Am. Physicians 103, 96–101 (1990).

    CAS  PubMed  Google Scholar 

  24. Wykrzykowska, J.et al. Early regeneration of thymic progenitors in rhesus macaques infected with simian immunodeficiency virus. J. Exp. Med. 187, 1767–1778 (1998).

    Article  CAS  Google Scholar 

  25. Bonyhadi, M.et al. HIV induces thymus depletion in vivo. Nature 363, 728–732 (1993).

    Article  ADS  CAS  Google Scholar 

  26. Aldrovandi, G. M.et al. The SCID-hu mouse as a model for HIV-1 infection. Nature 363, 732–736 (1993).

    Article  ADS  CAS  Google Scholar 

  27. Pakker, N.et al. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nature Med. 4, 208–214 (1998).

    Article  CAS  Google Scholar 

  28. Gorochov, G.et al. Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nature Med. 4, 215–221 (1998).

    Article  CAS  Google Scholar 

  29. Withers-Ward, E.et al. Transient reneweal of thymopoiesis in HIV-infected human thymic implants following antiviral therapy. Nature Med. 3, 1102–1109 (1997).

    Article  CAS  Google Scholar 

  30. Han, S.et al. V(D)J recombinase activity in a subset of germinal center B lymphocytes. Science 278, 301–305 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Wong for monoclonal antibody 12F6; M. Gately for rhIL-2; F. Scott, J. McKinsey, A. Rahimi, S. Norris, G. Sempowski, J. Tomasch and M. Zupancic for sample collection and processing; A. Mobley and B. Darnell for FACS support; B. Dawson for viral load measurement; R.Scheuermann and D. Sodora for advice; and all the study participants for their cooperation. This work was supported by grants from the NIH and the American Foundation for AIDS Research. R.A.K., M.B.F. and J.A.Z. are Elizabeth Glaser Scientists of the Pediatric AIDS Foundation.

Author information

Authors and Affiliations

  1. Departments of Medicine, The University of Texas Southwestern Medical Center, Dallas, 75235, Texas, USA

    Daniel C. Douek, Philip H. Keiser, Earl A. Gage & Richard A. Koup

  2. Departments of Pathology, The University of Texas Southwestern Medical Center, Dallas, 75235, Texas, USA

    Richard D. McFarland & Louis J. Picker

  3. Department of Medicine, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Janice M. Massey & Barton F. Haynes

  4. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Michael A. Polis

  5. Department of Microbiology, University of Minnesota Medical School, Minneapolis, 55455, Minnesota, USA

    Ashley T. Haase

  6. Department of Medicine, Emory University School of Medicine, Atlanta, 3022, Georgia, USA

    Mark B. Feinberg

  7. Departments of Pediatrics and Molecular Medicine, The University of Massachusetts Medical Center, Worcester, 01605, Massachusetts, USA

    John L. Sullivan#

  8. Division of Hematology-Oncology, Department of Medicine UCLA School of Medicine and UCLA Institute, Los Angeles, 90095, California, USA

    Beth D. Jamieson & Jerome A. Zack

  9. Department of Microbiology and Molecular Genetics, UCLA School of Medicine and UCLA Institute, Los Angeles, 90095, California, USA

    Jerome A. Zack

Authors
  1. Daniel C. Douek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard D. McFarland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip H. Keiser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Earl A. Gage
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Janice M. Massey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barton F. Haynes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael A. Polis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ashley T. Haase
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mark B. Feinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John L. Sullivan#
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Beth D. Jamieson
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jerome A. Zack
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Louis J. Picker
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Richard A. Koup
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard A. Koup.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Douek, D., McFarland, R., Keiser, P. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1998). https://doi.org/10.1038/25374

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/25374

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing